Asthma is a disease of airway smooth muscle dysfunction. The prevalence of asthma is between 6-9% of Americans. Asthma leads to significant morbidity and mortality with estimated healthcare and lost opportunity costs of 10.7 billion dollars annually (based on data from 1985-1994) in the United States. (See Weiss et al., 2000). Improved therapies are necessary to reduce suffering and lost productivity in asthma patients. Hypertrophy, hyper-reactivity, pathological remodeling, airway obstruction and inflammation are well established smooth muscle phenotypes in asthma patients, but a unifying biological rationale for these phenotypes was unknown. Present therapies are focused on ‘upstream’ targets, such as G-protein-coupled receptors (e.g., histamine, adrenergic leukotriene), glucocorticoid receptors and reactive oxygen species that activate signaling pathways important for selective smooth muscle responses in asthma. However, these therapies have not reversed the increase in asthma-related morbidity or mortality. Here it is shown that calmodulin kinase II (CaMKII) is a previously unrecognized, but critical downstream determinant of smooth muscle asthma phenotypes. These findings demonstrate that CaMKII contributes to bronchial hyper-reactivity in vivo and that CaMKII increases mucous accumulation and activates hypertrophic and proinflammatory gene programs in smooth muscle in vitro and in vivo. These findings suggest that CaMKII inhibitors may be utilized in methods for treating asthma and other pulmonary diseases or disorders.
Clinical outcomes in asthma have been linked to increased reactive oxygen species (ROS), airway hyper-reactivity, inflammation and mucous gland hyperplasia, but no previous work has identified a molecular mechanism linking these pro-asthmatic factors. The multifunctional Ca2+ and calmodulin dependent protein kinase II (CaMKII) is activated reactive oxygen species (ROS) generated by NADPH oxidase. (See Erickson et al., 2008).
Here, calmodulin kinase II (CaMKII) is shown to be a previously unrecognized, but critical downstream determinant of asthma phenotypes. The results presented here demonstrate that CaMKII contributes to bronchial hyper-reactivity in vivo and that CaMKII is activated by ROS due to NADPH oxidase. Furthermore, activated CaMKII contributes to mucous gland hyperplasia and pulmonary eosinophilia. The results presented here also show that CaMKII inhibition reduces these asthma responses. These findings suggest that CaMKII inhibitors may be utilized in methods for treating asthma and other pulmonary diseases or disorders.